The objective is to study the metabolism, distribution and excretion of the narcotic antagonists, naloxone and naltrexone. One of the main metabolism pathways studied will be the reduction of these compounds to 6 alpha or 6 beta-hydroxy products. The enzymes involved are stereoselective for product formation and we will determine if substrate stereoselectivity exists also. Since species differences occur in the amount and kind of enzyme present to reduce naloxone, a phylogenetic survey will be performed to pick out the most useful animals to study more intensively. This approach provides the opportunity to assess allosteric effects on enzyme function while at the same time considering stereospecific binding of the substrate. The in vitro enzyme work will be supported by in vivo studies where the consequence of effects of other drugs on naloxone metabolism may be observed. Biliary and urinary excretion studies will be aimed at implicating changes produced by drug treatment in the liver and kidney respectively. The mechanism by which morphine pretreatment enhances brain concentrations of naloxone will be investigated. Since the guinea pig liver cytosol preparations yield 6-alpha-naloxol from naloxone, we will see by which means the guinea pig excretes primarily 6 beta naloxol, the other epimer in vivo. All of these studies are aimed at achieving a better understanding from the metabolism point of view of the pharmacological action of naloxons and naltrexone.